Background. Interactions between HIV infection and methamphetamine abuse may affect neurocognitive function adversely. The studies proposed here will evaluate two general mechanisms by which these interactions may occur in vivo: (1) through damage mediated by soluble immune mediators known as cytokines and chemokines; and (2) through neuronal excitotoxicity. By determining levels of specific markers in cerebrospinal fluid (CSF) among HIV-infected (HIV+) methamphetamine dependent subjects (METH+), and by comparing them to HIV+/METH- and HIV-/METH+ subjects, we will delineate the relative importance of immune dysregulation and glutamatergic excitotoxicity in the pathogenesis of neurocognitive impairment in such individuals. Goals. The principal objectives of this research are 1) to delineate the effects of HIV infection and METH dependence on selected CSF markers; and, 2) to determiine whether these differences are linked to a higher incidence of syndromal neurocognitive disorders and neuropsychological impairment in HIV+/METH dependent subjects. Methods. We will obtain CSF and blood samples at baseline and at longitudinal follow-up visits on all subjects recruited to the 5-year Program Project. We will quantitate levels of tumor necrosis factor alpha (TNF-alpha) and its type 2 soluble receptor (sTNFR2), as well as macrophage inflammatory protein alpha (MIP-1alpha), and MIP-1beta in all samples using well-characterized immunoassays. In addition, we will collaborate with other labs to obtain measures of the glutamatergic neuronal excitotoxin, quinolinic acid. Significance. Methamphetamine profoundly affects central dopaminergic and glutamatergic neurotransmission. In addition, it may modulate the secretion of immune mediators such as cytokines through molecular signaling mechanisms that can, in turn, alter the clinical course of HIV CNS disease. Since methamphetamine is concentrated and sequestered in the central nervous system, and since HIV itself is associated with neuronal excitotoxicity and cytokine dysregulation, there is considerable potential for the pathophysiological effects of methamphetamine in HIV infected individuals to be amplified in the brain. Achieving a better understanding of the nature and importance of these effects may help lead to the development of: 1) improved ways of treating HIV infection in METH users; 2) enhanced and earlier recognition of neurocognitive disorders and how they may result from interactions between METH dependence and HIV infection; and, 3) greater awareness of the deleterious consequences of METH in HIV infection.